Helen Mactier, MD, FRCPCHPeter Galloway, MB, FRCPEdRuth Hamilton, MSc, CPhys

Lawrence Weaver, MD, DSc, FRCPDepartments of Child Health, Biochemistry, and Clinical PhysicsPrincess Royal Maternity and Royal Hospital for Sick Children

Glasgow, UKYMPD1377

10.1016/j.jpeds.2004.12.036

REFERENCES1. Ambalavanan N, Kennedy K, Tyson J, Carlo WA. Survey of vitamin A

supplementation for extremely-low-birth-weight infants: is clinical practice

consistent with the evidence? J Pediatr 2004;145:304-7.

2. Greene HL, Phillips BL, Franck L, Fillmore CM, Said HM, Murrell

JE, et al. Persistently low blood retinol levels during and after parenteral

administration of very low birth weight infants: examination of losses into

intravenous administration sets and a method of prevention by addition to

a lipid emulsion. Pediatrics 1987;79:894-900.

Reply

To the Editor:We appreciate the comments by West and Cummings1

andMactier et al2 on our survey of vitamin A use in extremely-low-birth-weight infants.3 We agree with Mactier that moreresearch is required on the pharmacology of vitamin A tooptimize the dose and route of administration in extremelypremature infants and appreciate the caution of West andCummings in the introduction of new therapies in neonates.

We welcome the investigative work of Mactier et al onthe intravenous vitamin A formulation. Their results indicatethat the manufacturer’s recommended dose of 920 IU/kg/daywas not sufficient to maintain adequate plasma retinol levels inmost infants. In the National Institute of Child Health andHuman Development (NICHD) vitamin A trial,4 the controlgroup received about 1000 IU/kg/day (enteral plus parenteral)versus 4000 IU/kg/day in the vitamin A group. However, eventhe higher intake in the supplemented group was associatedwith low vitamin A levels (serum retinol <20 mcg/dL) in 25%of the infants. Our subsequent study comparing even higherintakes (10,000 IU 3 times a week) to the standard regimen of5000 IU given intramuscularly 3 times a week showed that thehigher doses did not increase vitamin A concentrations orreduce the incidence of vitamin A deficiency.5 One possibleexplanation for why these high intakes of vitamin A do notimprove serum levels may be that serum levels of the vitamin Atransport proteins retinol-binding protein and transthyretin aredecreased by inflammation6 (ie, they are negative acute-phasereactants), and inflammation is common in these extremelypremature infants. Better methods may need to be developedto optimize transport and delivery of administered vitamin Ato tissues. It also needs to be determined whether improvingdelivery to the tissues further improves clinical outcomeswithoutintroducing toxicity.

We consider the evidence for the safety of vitaminA administration to be stronger than the evidence for the

To the Editor:In their paper, Ambalavanan et al1 conclude that current

clinical practices for vitamin A supplementation in extremely-low-birth-weight (ELBW) infants are inconsistent withavailable evidence. We disagree.

The authors’ support for the use of intramuscularvitamin A in ELBW infants is the metaanalysis by Darlowand Graham,2 which is largely weighted toward the authors’own study and includes studies in larger infants and alternatedosages and routes. Of all outcomes analyzed, only 2 showedmarginal risk reduction: death or oxygen supplementation at1 month (0.93; CI, 0.88-0.99) and oxygen need at 36 weekspostmenstrual age (0.87; CI, 0.77-0.99). The conclusion thatthe number needed to treat (NNT) is ‘‘14 to 20 to preventadverse pulmonary outcomes’’ is a distortion of the statistics.In reality, these numbers represent mean estimates from 2different outcomes, not the actual range for a given outcome.Those ranges are: death or oxygen need at 1 month(20;10,100); oxygen need at 36 weeks postmenstrual age(14;7,100). Thus, the NNT may be as high as 100.

In their metaanalysis, Darlow and Graham concludethat universal vitamin A supplementation for ELBW infantsis not supported by that data, but rather individualizeddecisions on the basis of local bronchopulmonary dysplasiarisk with the ‘‘benefits of a modest reduction in this outcomebalanced against lack of other proven benefits and theacceptability of treatment.’’ It appears the survey respondentsagree.

Finally, more study into the pharmacology of vitaminA is necessary before widespread use is considered. A thera-peutic window has yet to be defined in the ELBW population.Current supplementation practices result in unpredictableserum levels. For a vitamin with known toxicity, supplemen-tation can have significant risks. Unfortunately, neonatology

Letters

has a history of tragic effects for therapies thought initially tobe safe.

Todd West, MDJames Cummings, MD

Department of Pediatrics Neonatal DivisionEast Carolina UniversityGreenville, NC 27834

YMPD137810.1016/j.jpeds.2004.12.037

REFERENCES1. Ambalavanan N, Kennedy K, Tyson J, Carlo W. Survey of vitamin A

supplementation for extremely-low-birth-weight infants: is clinical practice

consistent with the evidence? J Pediatr 2004;145:304-7.

2. Darlow BA, Graham PJ. Vitamin A supplementation for preventing

morbidity and mortality in very low birthweight infants. Cochrane Database

Syst Rev 2002;4:CD000501.

847